The monoclonal gammopathies are naturally occuring human B-cell disorders of Ig synthesis predominantly of elderly humans. Because of a high incidence of transformation into frank malignant lymphoproliferation they may be considered as premalignant diseases. Two such gammopathies are the mixed IgM-IgG and monoclonal IgG, cryoglobulinemias. The basis for the malignant transition in these disorders is unknown. However, prospective studies at the protein and cellular levels of patients in early stages of their disease, and patients whose diseases are becoming more aggressive and are clinically in a benign to malignant transition, should provide interesting information concerning the development of malignancy. Since these diseases involve the elderly, the ontologic and evolutionary expression, regulation, and gene changes of a normal light chain marker with nearly a 100% involvement in the mixed IgM-IgG cryoglobulinemias will be studies in healthy young, middle-aged, and older volunteers to clarify the basis of its involvement in this disease. In patients with the both types of cryoglobulinemia the changes which develop at the cellular level in the genes and in the gene product i.e. the cryoglobulins, will be studied prospectively in order to detect aberrations which would signal the development of malignancy. In these experiments transforming gene presence and activation, possible gross immunoglobulin gene rearrangements, comparative protein synthetic rates at the cellular level for normal Ig and cryoglobulin Ig, and the detection of mutated protein structure will be studied. As a final goal, the cellular presence and localization of the gene product which has been translocated to and replaced, the variable region of an immunoglobulin lambda light chain during the transition from a monoclonal IgG cryoglobulinemia to a plasma cell leukemia will be studied. Cumulatively the studies provide an ideal human disease model for study of the influence of aging and aberrant immunoglobulin synthesis on the development of B-cell malignancies.